Pulmonary diseases or conditions span a range of lung-related diseases, including asthma and chronic obstructive pulmonary disease (COPD), which affect millions of people throughout the world.
For example, over 300 million people worldwide suffering from asthma. It is predicted that the prevalence will increase to about 400 million in the next decade. Asthma is a chronic airway disorder identified by recurrent wheeze and intermittent air flow limitation. It is characterized by airway inflammation, mucus hypersecretion, and airway hyperresponsiveness (AHR). Studies have shown that these clinical manifestations are, at least in part, inflammatory responses mediated by T-helper type 2 (Th2) cells together with mast cells, B cells and eosinophils, as well as a number of inflammatory cytokines and chemokines.
Currently, there are three anti-inflammatory agents for controlling asthma, which include inhaled steroids, cysteinyl-leukotriene receptor antagonist and cromolyn. However, the therapeutic efficacies of cysteinyl-leukotriene receptor antagonist and cromolyn are highly variable and may be limited to certain subgroup of patients. In addition, 5-10% of the asthmatics are not well-controlled by current drug treatment and they require oral steroids during exacerbation. Oral steroid usage is commonly associated with a diversity of adverse effects, most notably increases in appetite, stomach ulcers, difficulty sleeping (insomnia), changes in mood and behavior, flushing (redness) of the face, and short-term weight gain due to increased water retention. If taken for long periods of time, steroid use may lead to glaucoma, cataracts, high-blood pressure, heart disease, diabetes mellitus, obesity, acid reflux/GERD, osteoporosis, myopathy, increase in certain types of infections, and cushing syndrome.
COPD is a medical condition that is generally considered to include one or both of chronic bronchitis and emphysema. Chronic bronchitis is characterized by a persistent (such as more than one year) productive cough that is not due to a medically defined cause such as a microbial infection or carcinoma. Emphysema is an abnormal permanent non-uniform enlargement of air spaces distal to the terminal bronchioles, including destruction of the walls of the air spaces. COPD is caused by noxious particles or gas, most commonly from tobacco smoking, which triggers an abnormal inflammatory response in the lung. The natural course of COPD is characterized by occasional sudden worsening of symptoms called acute exacerbations, most of which are caused by infections or air pollution.
There is currently no cure for COPD and the only measures that have been shown to reduce mortality are smoking cessation and supplemental oxygen. COPD is treated with bronchodilators such as beta-2 agonists and/or anticholinergics. Beta-2 agonist stimulate beta-2 receptors while anticholinergics block stimulation from cholinergic nerves both are medicines that relax smooth muscle around the airways, increasing air flow. While these agents can ameliorate certain symptoms to some degree, they are not effective to halt progression of COPD.
Methylxanthines (a class of derivatives of xanthine and alkaloids) have often been used as bronchodilators. Methylxanthines relax smooth muscle, stimulate the central nervous system, stimulate cardiac muscle, and act on the kidneys to promote diuresis. Their usefulness in promoting relaxation of bronchial smooth muscle is of benefit in the management of asthma.
Methylxanthine theophylline is an established medicament for therapy of obstructive diseases of the respiratory tract. Theophylline is a competitive but non-selective inhibitor of several types of phosphodiesterases, the enzymes that degrade cAMP. Increased concentrations of cAMP may mediate the observed bronchodilation. Other proposed mechanisms of action of theophylline include inhibition of the release of intracellular calcium and competitive antagonism of the bronchoconstrictor adenosine.
Theophylline is a relatively low-cost treatment and can be administered in a sustained-release preparation that gives a duration of around 12 hours. However, theophylline has a number of side effects. The adverse gastrointestinal effects of theophylline include nausea, vomiting, abdominal pain, cramping, and diarrhea. Adverse central nervous system effects include insomnia, headache, dizziness, nervousness, and seizures, which are often more severe in children. Seizures may occur as the initial sign of theophylline toxicity without any other preceding signs and symptoms. Increased tremor in the patient's dominant hand has been reported. Cardiovascular and pulmonary adverse effects include tachycardia, arrhythmias, and tachypnea. Because of these toxicities, theophylline is often used as a second or third line asthma medication.